ALUMINIUM CONTAINING PHARMACEUTICAL PREPARATION WITH CONTROLLED RELEASE

Abstract: A pharmaceutical preparation containing at least one aluminium compound for antacid and/or abstringent and adsorbent actions is manufactured by treating 2-300 parts by weight of a water-swellable compound of limited swelling ability with 2-50 parts by weight of water and thereafter admixing it with a powder comprising at least one of the group consisting of 100 parts by weight of said at least one aluminium compound, 2-150 parts by weight of at least one phosphate compound and at least one auxiliary material. The mixture may be granulated and dried, and thereafter either pressed to tablets or filled into capsules; it may also be transformed into a suspension.

Description: Aluminium containing pharmaceutical preparation with controlled release FIELD OF THE INVENTION The invention relates to an antacid and/or adstringent and absorbent pharmaceutical preparation containing at least one aluminium compound, as well as a process for the production of such preparations. BACKGROUND OF THE INVENTION The disequilibirum between protective and aggressive fac- tors, such as hydrochloric acid, pepsin, bile acid, lyso- lecithin, nicotine, alcohol, stress, Helicobacter pylori etc. leads to different pathogenic events, such as ulcer, in the gastroduodenal area. Most antacid preparations used for the treatment of ulcer and pre-ulcer hyperacidity contain aluminium compounds. However, when aluminium is taken into the organism and absorbed, this may cause osteomalacia, osteodystrophia, neuropathy, Alzheimer disease etc. These disadvantages are described by C.Gitzinger, Fortschritte der Medizin, 105, 3/Suppl.19/,1987; and by W.Kurtz, ibid. 105, 5/Suppl.19/,1987. According to EP-Al-220,849, the probability of aluminium absorption and hence of unwanted side effects is increased with decreasing the final pH in the aluminium-based (e.g. aluminium hydroxide, magnesium-aluminium-hydrate, magaldrate etc.) liquid preparation (oral suspension) to pH=2.20-3.25 assuming cytoprotective effects. According to US-A-4,704,278, the same consequence occurs when the system contains a significant amount of citrate, which is added partly from a colloidal point of view, partly to ensure a quick start of the action. All factors increas- ing the solubility of aluminium compounds, such as the citrate ion, increase the risk of aluminium absorption. The process according to US-A- ,639,362 proposes combined molecules of magnesium and aluminium components such as mag¬ aldrate) , in which the aluminium content is lower than in the usual antacid formulae. On the other hand, the higher magnesium content may result in an undesired laxative effect. It has therefore been one object of the invention to provide an antacid and/or adstringent and absorbent pharmaceutical preparation which avoids the drawbacks related to the ab¬ sorption of aluminium in the body of a patient. Another ob- ject of the invention relates to the provision of a pharma¬ ceutical preparation with sustained release of the antacid and/or adstringent and absorbent compounds. SUMMARY OF THE INVENTION These objects are achieved by the inventive measures based on the surprising novel recognition that the dissolution of absorbable aluminium in aqueous media can significantly be decreased or completely inhibited by applying certain types of macromolecular hydrocolloids and water-soluble and/or water-insoluble phosphate compounds in the presence of each other. This phenomenon was observed in every case, i.e. in a tablet as well as in a suspension preparation, when the aluminium compound was applied and treated in mixture with at least one hydrocolloid of limited swelling ability and at least one water-soluble and/or water-insoluble phosphate compound, resulting in a limited or inhibited aluminium release due to the contact with gastric fluids by swelling of the hydro- colloid. The limited swelling ability is influenced by the pH and the presence of Al 3+ and can be characterized for the various hydrocolloids by viscosimetry. Usually, about 10% of the hydrocolloids - given as examples hereinafter - are in¬ deed swelled. The principle of the invention is a phosphate delivery system controlled by the swelling mechanism of the hydro- colloid. BRIEF DESCRIPTION OF THE DRAWINGS In Fig.1, the top left rectangle symbolizes the magaldrate example. Excess acid (AC) in the gastric fluid is neutralized (N) by the OH ~ -flux. The resulting Al3 + - flux is bound by the phosphate P and the swelled (arrow B) hydrocolloid HY to the phosphate/hydro- colloid/aluminium system (PHAS) . The phosphate/ hydrocolloid system (P+HY) controls the dissolution and binding of the aluminium as shown in Fig.2 (left of the dotted line: stomach ST; right of the dotted line: intestines IN) partly through an oscil¬ lating reaction mechanism influenced by the change of the intragastric pH-value, partly by binding the aluminium to the hydrocolloid, advantageously to a crosslinked polymer. Fig.3 shows the principle of the aluminium capture based partly on the significant difference in the solubility of aluminium hydroxide and aluminium phosphate; partly, it is also based on the function of the hydrocolloid-phosphate system, which binds the aluminium and is activated by the swelling of the hydrocolloid. The described aluminium capturing system does not decrease the acid neutralization ca¬ pacity of the aluminium compound at the acidic pH of the stomach (ST) but inhibits the absorption of alu- minium from the stomach (ST) and the duodenum (inte¬ stines (IN) , see Fig.2) of higher pH. Table I. - Change of the aluminium amount excreted by the urine of 5 patients over 24 hours after administration of 750 mg magaldrate compared to the control value of the pre¬ vious day: μg Al/24 h eliminated by urine Subject magaldrate magaldrate with the phosphate-hydrocolloid system ace. example 3 #1 + 13.8 + 8.6 #2 + 19.2 + 9.0 #3 + 4.0 - 7.1 #4 + 13.0 - 22.2 #5 + 18.0 + 14.0 Average: + 13.6 + 0.46 s χ (S.E.M) 2 .677 μg 6.683 μg t-value experimental 5.081 0.0688 Probability <0.05 >0.05 Difference siσnificant not siσnificant s χ (S.E.M.) is the standard deviation of the mean value; the t-value is the Student-t at 5% significance level. The aluminium compound may be selected from a wide range of inorganic and organic salts or complex compounds, such as aluminium hydroxide, aluminium glycinate (dihydroxyaluminium aminoacetate hydrate, USP XXII p. 445) , aluminiumsodium trisilicate, aluminium hydroxycarbonate (dihydroxyaluminium sodium carbonate, USP XXII p.447) , basic aluminium carbonate gel (USP XXII p.50) , aluminium phosphate (USP XXII p.53) , aluminium magnesium silicate (B.P.), natural or synthetic aluminium- and magnesium-containing compounds, preferably aluminiummagnesium hydroxycarbonate (hydrotalcite) and aluminiummagnesium hydroxysulphate (magaldrate) . The water-swellable compounds may be selected from the group comprising cellulose glycolic acid, starch glycolic acid, polyacrylic acid, copolymers of acrylic acid-methacrylic acid, alginic acid (polymannuronic acid, USNF XVII) , poly- vinylpyrrolidone, calcium alginate (BPC) , sodium alginate (USNF XVII) , Carbopol (R) 934P (carbomer, USNF XVII) , carb- oxymethylcellulose calcium (USNF XVII) , carboxymethylcellu- lose sodium (carmellose, USP XXII) , carrageenan (USNF XVII) , croscarmellose sodium (USNF XVII,Ac-Di-Sol (R) ) , cross-linked polyvinylpyrrolidone (USNF XVII, Polyplasdone XL (R) ) , hydroxypropylmethylcellulose (USP XXII) , carboxymethylcellu- lose sodium of low substitution grade (Nymcel ZSB-1θ (R) )# sodium starch glycolate (USNF XVII, Primojel (R) ) , tragacanth (USNF XVII), xanthan gum (USNF XVII). The phosphate compound may be selected from the group com¬ prising mono-, di- and tribasic calcium phosphate; mono-, di- and tribasic magnesium phosphate; mono- and dibasic sodium phosphate; mono- and dibasic potassium phosphate; mono- and dicalcium glycerophosphate. Auxiliary materials may be disintegrants such as starch, microcellulose, cross-linked polyvinylpyrrolidone etc.; tableting aids, such as lubricants, e.g. talc, magnesium stearate etc.; sweeteners such as saccharose, glucose, sac¬ charin-sodium, sodium cyclamate, aspartame etc.; flavouring agents such as lemon, orange and cassis aroma; fillers such as lactose. DETAILED DESCRIPTION OF THE INVENTION The invention is further explained by way of the following examples. Example 1 500g hydrotalcite and 70g tribasic calcium phosphate powder (components of the inner phase) are homogenized. 90g of cross-linked polyvinylpyrrolidone are swelled with 60-75 ml water (required for wet granulation) during 2 hours and then mixed with the powder mixture and kneaded. The wet mass is granulated by passing it through a sieve with openings of 1.4 mm. The granules are dried to a moisture content of 2.5% and then regranulated through a sieve with openings of 0.8 mm. 10g of cross-linked polyvinylpyrrolidone, 20g talc and 1Og magnesium stearate (powder components of the outer phase) are passed through a sieve with openings of 0.32 mm and mixed with the dry granules. The mixture is compressed to give 1000 tablets each of 0.7 g average weight. Example 2 The same procedure is followed as in Example 1 with the following compounds (for 1000 tablets of 0.75 g average weight each) : Inner phase: aluminium hydroxycarbonate 600 g tribasic magnesium phosphate 34 g carboxymethylcellulose sodium of low substitution grade 10 g cross-linked carboxymethyl¬ cellulose sodium (Ac-Di-Sol (R) ) 10 g water 80-100 ml outer phase: potato starch (disintegrant) 50 g talc 24 g magnesium stearate 12 g Nymcel ZSB 10< R) 10 g Example 3 The same procedure is followed as in Example 1 with the following compounds (for 1000 tablets of 1.3 g average weight each) : Inner phase: magaldrate 750 g dibasic calcium phosphate 450 g Nymcel ZSB 10< R > 273 g water 80-100 ml outer phase: magnesium stearate 25 g Nymcel ZSB 1θ (R) 200 g water 80-100 ml Example 4 : The same procedure is followed as in Example 1 with the following compounds (for 1000 tablets for 1.5 g average weight each) : Inner phase: aluminium hydroxide 375 g tribasic calcium phosphate 100 g Nymcel ZSB 1θ (R) 200 g water 80-100 ml outer phase: microcrystalline cellulose Avicel PH 102< R > 825 g Example 5 The same procedure is followed as in Example 4 with the following compounds (for 1000 tablets of 1.5 g average weight each) , with the exception that double-layered tablets are formed. The antacid active ingredient is pressed as the first layer, onto which the second layer containing the other components and the microcrystalline cellulose is pressed: First layer: aluminium hydroxide 375 g microcrystalline cellulose (Avicel PH 102 (R) ) 400 g second layer:Nymcel ZSB 1θ (R) 200 g tribasic calcium phosphate 100 g water 80-100 ml microcrystalline cellulose (Avicel PH 102 (R) ) 425 g Example 6 The same procedure is followed as in Example 4 - with the exception that three-layered tablets are formed - with the following compounds (for 1000 tablets of 1.5 g average weight each) : First layer: Aluminium hydroxide 375 g microcrystalline cellulose (Avicel PH 102 (R) ) 400 g second layer: ymcel ZSB 1θ (R) 200 g microcrystalline cellulose (Avicel PH 102 (R >) 250 g water 80-1 00 ml third layer: tribasic calcium phosphate 1 00 g microcrystalline cellulose (Avicel PH 102 (R >) 175 g Example 7 The same procedure is followed as in Example 4 - with the exception that the particles of the phosphate, compound are coated by spraying on them (and afterwards drying) an isopropanolic solution of Eudragit L100-55 - with the following compounds (for 1000 tablets of 1.5 g average weight each) : Inner phase (aluminium) : aluminium hydroxide 375 g inner phase (phosphate) : tribasic calcium phosphate 100 g coating: Eudragit L 100-55 6 7.5 g isopropanol 60 g Nymcel ZSB 10< R) 200 g water 80-100 ml outer phase: microcrystalline cellulose (Avicel PH 102< R >) 825 g Example 8 The same procedure is followed and composition used as in Example 7 with the exception that the tribasic calcium phosphate is coated with a solution of 4.5 g celluloseacetatephtalate in 30 ml of acetone. Example 9 1000 ml of an antacid suspension are prepared, having the following composition: magaldrate 200 g cross-linked carboxymethylcellulose sodium (Ac-Di-Sol (R) ) 50 g tribasic calcium phosphate 75 g tribasic magnesium phosphate 75 g hydroxy-propylmethylcellulose 4000 12 g methylparaben 10 g alcohol 10 g water, deionized to 1000 ml Ac-Di-Sol (R) is swelled in a 2% solution of the viscosity increasing agent HPMC 4000 (viscosity 4000 cP) ; then, the homogenous mixture of the various powder components is suspended in it. Finally, the alcoholic solution of the microbiological preservative (methylparaben) is added. Example 10 Example 9 is repeated except that the composition differs as follows: aluminium hydroxide 100 g alginic acid 140 g monobasic sodium phosphate 140 g hydroxy-propylmethylcellulose 4000 12 g propylparaben 2.5 g methylparaben 2.5 g alcohol 10 g water, deionized to 1000 ml The alginic acid is first swelled in the acidic hydroxy- propylmethylcellulose solution containing monobasic sodium phosphate to produce the limited swelling form of the hydrocolloid. Example 11 The following powder components for 1000 capsules: aluminium hydroxide 250 g monobasic sodium phosphate 100 g alginic acid 100 g are mixed and granulated in the dry state or by adding water and drying; then, 0.5 g Aerosil R972 (R) lubricant is mixed with the dry granules. A 0.40-0.45 g portion of the mixture is filled into a hard gelatine capsule. Example 12 A tablet preparation with antacid and adstringent effect is formulated with the following composition for 1000 tablets: aluminium hydroxide 500 g aluminium glycinate 500 g cellulose glycolic acid 250 g Carbopol 934p (R) 25 g tribasic magnesium phosphate 100 g magnesium stearate 23 g Aerosil R972< R) 2 g The process is completed in the usual way: the cellulose glycolic acid is swelled in the Carbopol 934p (R *> solution. This liquid is used for the wet granulation of the powder mixture. The tablet preparation is formed as described in Example 1.

Claims: C L A I M S 1. Process for the manufacture of a pharmaceutical preparation containing at least one aluminium compound for antacid and/or adstringent and absorbent action, wherein 2-300 parts by weight of a water-swellable compound of limited swelling ability selected from the group consisting of the dry compound and the compound after treatment with 2-50 parts by weight of water is admixed with 100 parts by weight of said at least one aluminium compound and 2-150 parts by weight of at least one phosphate compound. 2. Process according to claim 1 , wherein at least one aux¬ iliary material selected from the group consisting of tableting vehicles, diluents, sweeteners and flavouring agents is further added to the mixture. 3. Process according to claim 1 or 2 wherein the mass is granulated and dried. 4. Process according to claim 1 , wherein said aluminium compound is selected from the group consisting of aluminium hydroxide, aluminium glycinate (dihydroxyalumi- nium aminoacetate hydrate) , aluminiumsodium trisilicate, aluminium hydroxycarbonate (dihydroxyaluminium sodium carbonate) , basic aluminium carbonate gel, aluminium phosphate, aluminium magnesium silicate, natural or syn- thetic aluminium- and magnesium-containing compounds, such as aluminiummagnesium hydroxycarbonate (hydrotalcite) and aluminiummagnesium hydroxysulphate (magaldrate) . 5. Process according to claim 1, wherein said water-swell- able compound is selected from the group consisting of cellulose glycolic acid, starch glycolic acid, polyacryl- ic acid, copolymers of acrylic acid-methacrylic acid, alginic acid, polyvinylpyrrolidone, calcium alginate, sodium alginate, carbomer, carboxymethylcellulose cal¬ cium, carboxymethylcellulose sodium (carmellose) , carra- geenan, croscarmellose sodium, hydroxypropylmethylcellu- lose, carboxymethylcellulose sodium of low substitution grade, sodium starch glycolate, tragacanth and xanthan gum. 6. Process according to claim 1 , wherein said phosphate is selected from the group consisting of mono-, di- and tri¬ basic calcium phosphate; mono-, di- and tribasic magne- sium phosphate; mono- and dibasic sodium phosphate; mono- and dibasic potassium phosphate; mono- and dicalcium gly- cerophosphate. 7. Process according to claim 6, wherein the particles of said phosphate are coated - per 100 parts by weight of said phosphate compound(s) - with 2.5 to 15 parts by weight of a sustained release coating material. 8. Process according to claim 1 , wherein the mixture is further granulated and dried. 9. Process according to claim 8, wherein the dried mixture is pressed to tablets. 10. Process according to claim 8, wherein the dried mixture is filled into capsules. 11. Process according to claim 1 , wherein the mixture is further transformed into an aqueous suspension. 12. Pharmaceutical preparation containing at least one alu¬ minium compound for antacid and/or adstringent and absor¬ bent action, wherein said aluminium compound is present in admixture with at least one water-swellable compound selected from the group consisting of hydrocolloids, syn- thetic polymers and natural polymers, and with at least one pharmaceutically acceptable phosphate compound. 13. Pharmaceutical preparation according to claim 12, wherein said aluminium salt is selected from the group consisting of aluminium hydroxide, aluminium glycinate (dihydroxyaluminium aminoacetate hydrate) , aluminiumsodium trisilicate, aluminium hydroxycarbonate (dihydroxyaluminium sodium carbonate) , basic aluminium carbonate gel, aluminium phosphate, aluminium magnesium silicate, natural or synthetic aluminium- and magnesium- containing compounds, such as aluminiummagnesium hydroxycarbonate (hydrotalcite) and aluminiummagnesium hydroxysulphate (magaldrate) . 14. Pharmaceutical preparation according to claim 12, wherein said water-swellable compound is selected from the group consisting of cellulose glycolic acid, starch glycolic acid, polyacrylic acid, copolymers of acrylic acid-methacrylic acid, alginic acid, polyvinylpyrroli¬ done, calcium alginate, sodium alginate, carbomer, carb¬ oxymethylcellulose calcium, carboxymethylcellulose sodium (carmellose) , carrageenan, croscarmellose sodium, hydroxypropylmethylcellulose, carboxymethylcellulose sodium of low substitution grade, sodium starch glycolate, tragacanth and xanthan gum. 15. Pharmaceutical preparation according to claim 12 wherein said phosphate compound is selected from the group consisting of mono-, di- and tribasic calcium phosphate; mono-, di- and tribasic magnesium phosphate; mono- and dibasic sodium phosphate; mono- and dibasic potassium phosphate; mono- and dicalcium glycerophosphate. 16. Pharmaceutical preparation according to claim 12 or 15, wherein the particles of said phosphate compound(s) are coated - per 100 parts by weight of said phosphate compound(s) - with 2.5 to 15 parts by weight of a sustained release coating material. 17. Pharmaceutical preparation according to claim 12, fur¬ ther comprising at least one auxiliary compound selected from the group consisting of tableting vehicles, dilu¬ ents, sweeteners and flavouring agents. 18. Pharmaceutical preparation according to claim 12, wherein any one compound of the group consisting of the aluminium compound, the phosphate compound and the auxiliary material is embedded in said swellable compound. 19. Pharmaceutical preparation according to claim 12, char¬ acterized in that it is in the form of a tablet. 20. Pharmaceutical preparation according to claim 12, char¬ acterized in that it is in the form of a suspension. 21. Pharmaceutical preparation according to claim 12, char- acterized in that it is contained in a capsule.

Inventors: ANTAL ISTVAN, PLACHY JANOS, RACZ ISTVAN, ANTAL, ISTVAN, PLACHY, JANOS, RACZ, ISTVAN
Applicants: ANTAL ISTVAN, PLACHY JANOS, RACZ ISTVAN, SYNEPOS AG, ANTAL, ISTVAN, PLACHY, JANOS, RACZ, ISTVAN, SYNEPOS AKTIENGESELLSCHAFT
Application year: 1994
Main classification: A61K33
IPC codes: A61K9, A61K31, A61K33, A61K47, A61P1